In recent years, a novel murine growth factor, designated thymic stromal lymphopoietin (TSLP), has been isolated. TSLP has been demonstrated to have a role in B cell development and maturation. The cytokine activity of murine TSLP is very similar to that of IL-7, which is required during proliferation and survival of pre-B cells (Friend et al., Exp. Hematol., 22:321-328, 1994). In addition, mature B lymphocytes fail to develop in the absence of either IL-7 or murine TSLP. It has further been shown that murine TSLP can replace IL-7 in sustaining B cell proliferative responses (Ray et al., Eur. J. Immunol. 26:10-16, 1996). Studies with IL-7 receptor (IL-7R) knockout mice indicate that IL-7, TSLP, or both, play a role in controlling the rearrangement of the T cell receptor-gamma (TCR.gamma) locus (Candeias et al., Immunology Letters 57: 9-14, 1997). Human TSLP has been cloned and sequenced (see U.S. Pat. No. 6,555,520). There is a need to determine the role in of TSLP human T cell development and maturation.
The primary immunologic abnormality resulting from infection by HIV is the progressive depletion and functional impairment of T lymphocytes expressing the CD4 cell surface glycoprotein (Lane et al., Ann. Rev. Immunol. 3:477, 1985). CD4 is a non-polymorphic glycoprotein with homology to the immunoglobulin gene superfamily (Maddon et al., Cell 42:93, 1985). Together with the CD8 surface antigen, CD4 defines two distinct subsets of mature peripheral T cells (Reinherz et al., Cell 19:821, 1980), which are distinguished by their ability to interact with nominal antigen targets in the context of Class I and Class II major histocompatibility complex (MHC) antigens, respectively (see Swain, Proc. Natl. Acad. Sci. 78:7101, 1981). For the most part, CD4 T cells display the helper/inducer T cell phenotype (Reinherz, supra), although CD4 T cells characterized as cytotoxic/suppressor T cells have also been identified (Thomas et al., J. Exp. Med. 154:459, 1981; Meuer et al., Proc. Natl. Acad. Sci. USA 79:4395, 1982). The loss of CD4 helper/inducer T cell function probably underlies the profound defects in cellular and humoral immunity leading to the opportunistic infections and malignancies characteristic of the acquired immunodeficiency syndrome (AIDS) (Lane et al., Ann. Rev. Immunol. 3:477, 1985). Studies of HIV-I infection of fractionated CD4 and CD8 T cells from normal donors and AIDS patients have revealed that depletion of CD4 T cells results from the ability of HIV-I to selectively infect, replicate in, and ultimately destroy this T lymphocyte subset (Klatzmann et al., Science 225:59, 1984).
The widespread use of highly active antiretroviral therapy (HAART) has dramatically improved the clinical course for many individuals infected with HIV (Berrey et al., J Infect Dis 183(10):1466, 2001). However, toxicities associated with long term HAART have put a high priority on the design and development of less toxic therapies. Among the “next generation” of anti-viral inhibitors is T-20 (Wild et al., Proc Natl Acad Sci USA 91(26):12676, 1994; Wild et al. Proc Natl Acad Sci USA 89(21):10537, 1992). However, there remains an acute need for additional therapeutic agents that can be used alone or in combination with HAART to increase CD4 activity and treat HIV-infected individuals.